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TargetMol—Signaling Pathway—CHIR-99021 (Cat. No. T2310, Cas. 252917-06-9), Precisely Targeted Cell Fate Reprogramming
1. Product Introduction
CHIR-99021(Cat. No. T2310, Cas. 252917-06-9), also known as Laduviglusib, CT99021, CHIR99021. CHIR-99021 (CT99021) is a Wnt / β-catenin signaling pathway activator and a GSK-3α / β inhibitor (IC50 = 10 / 6.7 nM) with selective and oral activity. CHIR-99021 can induce autophagy and enhance the self-renewal of mouse and human embryonic stem cells.
Molecular structure of CHIR-99021
2. Background Introduction
Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine / threonine protein kinase, including two isoforms of GSK-3α and GSK-3β, which plays a key regulatory role in various biological processes such as cell metabolism, proliferation, differentiation and apoptosis. Especially in the canonical Wnt / β-catenin signaling pathway, GSK-3 promotes its ubiquitination degradation by phosphorylating β-catenin, thereby inhibiting the activation of Wnt signaling. When Wnt signaling is activated or GSK-3 activity is inhibited, β-catenin is stably accumulated in the cytoplasm and translocated into the nucleus, thereby initiating target gene transcription and regulating embryonic development and stem cell fate determination. The precise regulation of this pathway is considered to be one of the important mechanisms to maintain stem cell pluripotency and tissue homeostasis. [1]
The diagram of Wnt signaling pathway [1]
CHIR-99021 (CHIR99021) is a highly selective GSK-3α / β small molecule inhibitor, which significantly inhibits its catalytic activity by competitively binding the GSK-3 kinase domain with ATP. The core mechanism of its action is to block the phosphorylation of β-catenin by GSK-3, thereby inhibiting its degradation, making β-catenin accumulate stably in cells and enter the nucleus, and activating TCF / LEF transcription factor-mediated Wnt target gene expression. This process can enhance the maintenance of pluripotency of stem cells and promote cell fate reprogramming and directional differentiation under certain conditions. In addition, CHIR-99021 can indirectly affect the expression of key proliferation-related genes such as c-Myc by regulating the Wnt / β-catenin downstream network, which has a wide application value in stem cell expansion and tissue regeneration research. [2]
3. Application References
Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model
Research Overview:
This study systematically investigated the protective and repair effects of highly selective inhibitor CHIR-99021 (CHIR99021) on lung regeneration in a mouse model of acute lung injury ( ALI ) induced by LPS. The results show that inhibition of GSK-3 activity by pharmacological means can effectively activate the Wnt / β-catenin signaling pathway in lung tissue, significantly promote the proliferation and differentiation of alveolar epithelial cells (especially AECII), thereby reducing tissue damage caused by inflammatory response and accelerating the structural reconstruction and functional recovery of lung function. These findings highlight the potential of targeted therapies that regulate GSK-3α / β inhibition and provide innovative approaches for the management of acute lung disease, especially in the late stage of no treatment. [3]
CHIR-99021 inhibits the effect of GSK-3 on lung proliferation [3]
Natural polyphenols naringin targeting GSK3β: an effective strategy for enhancing myoblast proliferation and myogenesis for cultured meat production
Research Overview:
This study focused on the role of natural polyphenolic compound naringin in muscle cell biology, and explored its application value as a potential regulatory molecule targeting GSK3β in the production of cultured meat (CM). Studies have found that Naringin can effectively inhibit the activity of GSK3β, thereby relieving its inhibition of Wnt / β-catenin signaling pathway, promoting the stability and nuclear translocation of β-catenin in cells, and then activating the expression program of myogenesis-related genes. Driven by this mechanism, Naringin significantly enhanced the proliferation of myoblasts and promoted their differentiation into mature muscle fibers (myogenesis). This study not only reveals the molecular mechanism of natural products regulating GSK3β-Wnt axis in muscle development, but also provides a potential strategy for optimizing the construction of muscle tissue in vitro and the production of cultured meat. [4]
In this article, CHIR-99021 (Cat. No. T2310) was used as a small molecule compound control for GSK3β inhibitors to screen the effects of different signaling pathway regulators on the proliferation and myogenic ability of myoblasts. The effects of three small molecules (TGF-β inhibitor SB431542, mTOR activator MHY1485 and GSK3β inhibitor CHIR-99021) on promoting the proliferation and differentiation of myoblasts were compared. The results showed that CHIR-99021 was most effective in inhibiting GSK3β activity and activating the Wnt / β-catenin signaling pathway. Therefore, CHIR-99021 was used as a standard compound to confirm the promotion effect of GSK3β inhibition strategy on muscle cell expansion, and on this basis, the possibility of replacing it with natural polyphenols (such as Naringin) as a food-grade safety additive was discussed.
Myogenic potential of C2C12 myoblasts treated with SB431542, MHY1485 and CHIR99021 [4]
4. References
[1] Wang B, Khan S, Wang P, Wang X, Liu Y, Chen J, Tu X. A Highly Selective GSK-3β Inhibitor CHIR99021 Promotes Osteogenesis by Activating Canonical and Autophagy-Mediated Wnt Signaling. Front Endocrinol (Lausanne). 2022 Jul 18;13:926622. doi: 10.3389/fendo.2022.926622. PMID: 35923616; PMCID: PMC9339598.
[2] Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A. The ground state of embryonic stem cell self-renewal. Nature. 2008 May 22;453(7194):519-23. doi: 10.1038/nature06968. PMID: 18497825; PMCID: PMC5328678.
[3] Fernandes R, Barbosa-Matos C, Borges-Pereira C, Carvalho ALRT, Costa S. Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model. Int J Mol Sci. 2024 Jan 20;25(2):1279. doi: 10.3390/ijms25021279. PMID: 38279281; PMCID: PMC10816825.
[4] Jiang, N., Bao, H., Lu, P., Li, Q., & Chen, Q. (2025). Natural polyphenols naringin targeting GSK3β: An effective strategy for enhancing myoblast proliferation and myogenesis for cultured meat production. Food Bioscience, 2025, 69, 106875.
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